Arsenic trioxide is indicated for the induction of remission and consolidation in adult patients with: newly diagnosed acute promyelocytic leukaemia (APL) at low to intermediate risk (white blood cell count ≤ 10 x 103/µl) in combination with all-trans retinoic acid (ATRA), relapsed/refractory acute promyelocytic leukaemia (APL) (previous treatment should have included retinoid an

ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion: Koncentrat do sporządzania roztworu do infuzji 1 mg/ml

Summary of the safety profile Adverse reactions associated with CTC Grade 3 and 4 occurred in 37% of patients with refractory/relapsed APL in clinical trials. The most commonly reported reactions were: hyperglycaemia, hypokalaemia, neutropenia and elevated alanine aminotransferase (ALT) levels. Leukocytosis occurred in 50% of patients with refractory/relapsed APL; it was determin

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion

Q: Warnings?

Patients with clinically unstable APL are at particular risk and will require more frequent monitoring of electrolytes and blood glucose and more frequent haematological, renal, coagulation and liver function tests. Leukocyte activation syndrome (APL differentiation syndrome) A total of 27% of patients with relapsed/refractory APL treated with arsenic trioxide reported symptoms similar to a syndro

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ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion — Description, Dosage, Side Effects | PillsCard

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX27 Mechanism of action The mechanism of action of arsenic trioxide is not entirely known.‍‍‍‍‍‍‍‍‍‍‍‍‍ Arsenic trioxide causes changes in morphology and fragmentation of deoxyribonucleic acid (DNA), which is characteristic of apoptosis in human promyelocytic leukaemia NB4 cells in vitro. Arsenic trioxide also causes damage to or degradation of the promyelocytic leukaemia/retinoic acid receptor alpha (PML/RAR-alpha) fusion protein. Clinical efficacy and safety Newly diagnosed APL patients who are not at high risk Arsenic trioxide was studied in 77 newly diagnosed APL patients at low to intermediate risk in a controlled, randomised, phase 3, non-inferiority clinical trial comparing the efficacy and safety of arsenic trioxide in combination with all-trans retinoic acid (ATRA) with the efficacy and safety of ATRA in combination with chemotherapy (e.g. idarubicin and mitoxantrone) (APL0406 study). Patients enrolled in the study had newly diagnosed APL confirmed by the presence of t(15;17), PML-RARα by RT-PCR or microgranular distribution of PML in the cell nucleus of leukaemic cells. No data are available on patients with variant translocations, such as t(11;17) (PLZF/RARα). Patients with significant arrhythmias, ECG abnormalities (congenital long QT syndrome, significant ventricular or atrial tachycardia current or in the medical history, clinically significant resting bradycardia (< 50 beats per minute), QTc > 450 ms on screening ECG, right bundle branch block plus left anterior hemiblock, bifascicular block) or neuropathy were excluded from the study. Patients in the ATRA + arsenic trioxide treatment group received oral ATRA at a dose of 45 mg/m2 daily and intravenous arsenic trioxide at a dose of 0.15 mg/kg daily until complete remission was achieved. During consolidation, ATRA was administered at the same dose for 2 weeks with a 2-week break, for a total of 7 cycles. Arsenic trioxide was administered at the same dose 5 days per week for 4 weeks with a 4-week break, for a total of 4 cycles. Patients in the ATRA and chemotherapy treatment group received intravenous idarubicin at a dose of 12 mg/m2 on days 2, 4, 6 and 8 and oral ATRA at a dose of 45 mg/m2 daily until complete remission was achieved. During consolidation, patients received idarubicin at a dose of 5 mg/m2 on days 1 to 4 and ATRA at a dose of 45 mg/m2 daily for 15 days. They then received intravenous mitoxantrone at a dose of 10 mg/m2 on days 1 to 5 and again ATRA at a dose of 45 mg/m2 daily for 15 days, and finally a single dose of idarubicin 12 mg/m2 and ATRA at a dose of 45 mg/m2 daily for 15 days. Each consolidation cycle was initiated upon haematological recovery from the previous cycle, defined as absolute neutrophil count > 1.5×109/l and platelets > 100×109/l. Patients in the ATRA + chemotherapy treatment group also underwent maintenance therapy for up to 2 years, consisting of oral mercaptopurine at a dose of 50 mg/m2 daily, intramuscular methotrexate at a dose of 15 mg/m2 weekly and ATRA at a dose of 45 mg/m2 daily for 15 days once every 3 months. Key efficacy results are summarised in Table 3 below: Table 3 Endpoint ATRA + arsenic trioxide (n = 77) [%] ATRA + chemotherapy (n = 79) [%] Confidence interval (CI) P-value p < 0.001 95% CI for for non-inferiority 2-year event-free survival (EFS) 97 86 difference, 2–22 percentage p = 0.02 points for superiority ATRA + arsenic trioxide Complete haematological remission (CHR) 100 95 p = 0.12 2-year overall survival (OS) 99 91 p = 0.02 2-year disease-free survival (DFS) 97 90 p = 0.11 2-year cumulative incidence of relapse (CIR) 1 6 p = 0.24 APL = acute promyelocytic leukaemia; ATRA = all-trans retinoic acid Relapsed/refractory APL Arsenic trioxide was studied in 52 APL patients who had previously been treated with an anthracycline and retinoids, in two open-label, single-arm, non-comparative studies. One was a single-investigator clinical trial (n = 12) and the other was a multicentre study conducted at nine institutions (n = 40). Patients in the first study received a median dose of arsenic trioxide of 0.16 mg/kg/day (range 0.06 to 0.20 mg/kg/day) and patients enrolled in the multicentre study received a fixed dose of 0.15 mg/kg/day. Arsenic trioxide was administered intravenously over one to two hours until the bone marrow was cleared of leukaemic cells, but for a maximum of 60 days. Patients with complete remission received an additional 25 doses of arsenic trioxide as consolidation therapy over a five-week period. Consolidation therapy was initiated 6 weeks (range 3–8) after induction in the single-centre study and 4 weeks (range 3–6) after induction in the multicentre study. Complete remission was defined as the absence of visible leukaemic cells in the bone marrow and peripheral recovery of platelets and white blood cells. Patients in the single-centre study had relapsed after 1–6 prior treatment regimens and two patients relapsed after stem cell transplantation. Patients in the multicentre study had relapsed after 1–4 prior treatment regimens and 5 patients relapsed after stem cell transplantation. The median age in the single-centre study was 33 years (age range 9 to 75 years). The median age in the multicentre study was 40 years (age range 5 to 73 years). A summary of results is presented in the following Table 4: Table 4 Single-centre study n = 12 Multicentre study n = 40 Arsenic trioxide dose in mg/kg/day (median, range) 0.16 (0.06 – 0.20) 0.15 Complete remission 11 (92%) 34 (85%) Time to bone marrow remission (median) 32 days 35 days Time to complete remission (median) 54 days 59 days 18-month survival 67% 66% Two paediatric patients (under 18 years of age) were enrolled in the single-centre study; both achieved complete remission. Five paediatric patients (under 18 years of age) were enrolled in the multicentre study; three of them achieved complete remission. No children under five years of age were treated. As subsequent treatment after consolidation, seven patients in the single-centre study and 18 patients in the multicentre study received additional maintenance therapy with arsenic trioxide. Three patients from the single-centre study and 15 patients from the multicentre study underwent stem cell transplantation after completion of arsenic trioxide treatment. The Kaplan-Meier median duration of complete remission in the single-centre study was 14 months; in the multicentre study it was not reached. At last follow-up, six of 12 patients from the single-centre study were alive, with a median follow-up duration of 28 months (range 25 to 29). In the multicentre study, 27 of 40 patients were alive with a median follow-up duration of 16 months (range 9 to 25). Kaplan-Meier estimates of 18-month survival for both studies are shown below. 100% 80% 60% 40% 20% Single Center Multicenter Study At Risk 12 40 Deaths 6 13 18-Month 67% 66% 0% 0 6 12 18 24 30 36 Months Legend: Single center – Single centre Multicenter Study – Multicentre study At risk – At risk Deaths – Deaths 18-month – 18 months Months – Months Cytogenetic confirmation of conversion to a normal genotype and detection of PML/RARα conversion to normal by reverse transcriptase-polymerase chain reaction (RT-PCR) are shown in Table 5 below. Cytogenetics after arsenic trioxide treatment Table 5 Pilot single-centre study n with complete remission = 11 Multicentre study n with complete remission = 34 Conventional cytogenetics [t(15;17)] Not performed 8 (73%) 31 (91%) Performed 1 (9%) 0% Non-evaluable 2 (18%) 3 (9%) RT-PCR for PML/ RARα Negative 8 (73%) 27 (79%) Positive 3 (27%) 4 (12%) Non-evaluable 0 3 (9%) Responses were observed across all age groups studied, ranging from 6 to 75 years. The response rate was similar for both sexes. There is no experience with the effects of arsenic trioxide in variant APL containing chromosomal translocations t(11;17) and t(5;17). Paediatric population Experience in children is limited. Of 7 patients under 18 years of age (range 5 to 16 years) treated with arsenic trioxide at the recommended dose of 0.15 mg/kg/day, 5 patients achieved a complete response (see section 4.2).

⚠️ Warnings

Patients with clinically unstable APL are at particular risk and will require more frequent monitoring of electrolytes and blood glucose and more frequent haematological, renal, coagulation and liver function tests. Leukocyte activation syndrome (APL differentiation syndrome) A total of 27% of patients with relapsed/refractory APL treated with arsenic trioxide reported symptoms similar to a syndrome called RA-acute promyelocytic leukaemia (RA-APL) or APL differentiation syndrome, characterised by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leukocytosis.‍‍‍‍‍‍‍‍‍‍‍‍‍ This syndrome can be fatal. In patients with newly diagnosed APL treated with arsenic trioxide and all-trans retinoic acid (ATRA), APL differentiation syndrome was observed in 19% of cases, including 5 severe cases. At the first signs that could suggest the onset of this syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultation findings or abnormalities on chest X-rays), arsenic trioxide treatment must be temporarily stopped and high-dose steroid therapy (dexamethasone 10 mg intravenously twice daily) must be immediately initiated, regardless of the white blood cell count; treatment must continue for a minimum of three days or longer until signs and symptoms have resolved. Where clinically indicated/as needed, concomitant diuretic therapy is also recommended. In the majority of patients, permanent discontinuation of arsenic trioxide during treatment of APL differentiation syndrome is not required. Once signs and symptoms have resolved, arsenic trioxide therapy may be restarted at a dose corresponding to 50% of the previous dose during the first 7 days. Thereafter, if the previous toxicity does not recur, arsenic trioxide treatment may be resumed at full dose. If symptoms recur, arsenic trioxide dosing must be reduced to the previous level. To prevent the development of APL differentiation syndrome during induction therapy, prednisone (0.5 mg/kg body weight daily throughout the induction period) may be administered to APL patients from day 1 of arsenic trioxide administration until the end of induction therapy. It is recommended not to combine steroid therapy with chemotherapy, as there is no experience with the administration of steroids and chemotherapy during the treatment of leukocyte activation syndrome induced by arsenic trioxide. Post-marketing experience suggests that a similar syndrome may occur in patients with other types of malignancies. Monitoring and treatment of these patients should be performed as described above. Electrocardiogram (ECG) abnormalities Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT interval prolongation can lead to a ventricular arrhythmia of the torsades de pointes type, which can be fatal. Prior anthracycline therapy may increase the risk of QT prolongation. The risk of developing torsades de pointes is related to the extent of QT prolongation, concomitant administration of medicinal products that prolong the QT interval (such as class Ia and III antiarrhythmics, e.g. quinidine, amiodarone, sotalol, dofetilide), antipsychotics (e.g. thioridazine), antidepressants (e.g. amitriptyline), certain macrolides (e.g. erythromycin), certain antihistamines (e.g. terfenadine and astemizole), certain quinolone antibiotics (e.g. sparfloxacin) and other individual medicinal products that prolong the QT interval (e.g. cisapride), a history of torsades de pointes, pre-existing QT prolongation, congestive heart failure, administration of potassium-depleting diuretics, amphotericin B or other conditions leading to hypokalaemia or hypomagnesaemia. In clinical trials conducted in relapsed/refractory patients, 40% of patients treated with arsenic trioxide experienced at least one prolongation of the corrected QT interval (QTc) exceeding 500 ms. QTc prolongation was observed between the first and fifth week after arsenic trioxide infusion, with return to baseline within eight weeks after arsenic trioxide infusion. One patient (who was concomitantly receiving several medicinal products including amphotericin B) developed asymptomatic torsades de pointes during induction treatment for relapsed APL with arsenic trioxide. In newly diagnosed APL, 15.6% of patients receiving arsenic trioxide in combination with ATRA (see section 4.8) exhibited QTc interval prolongation. In one newly diagnosed patient, induction treatment was discontinued due to severe QTc interval prolongation and electrolyte abnormalities on day 3 of induction therapy. Recommendations for ECG and electrolyte monitoring A 12-lead ECG must be performed and serum electrolyte levels (potassium, calcium and magnesium) and creatinine must be evaluated before starting arsenic trioxide treatment; existing electrolyte abnormalities must be corrected and, where possible, medicinal products that cause QT prolongation should be discontinued. The cardiac function of patients with risk factors for QTc prolongation or risk factors for torsades de pointes should be continuously monitored (by ECG). If the QTc interval is longer than 500 ms, corrective measures must be completed and the QTc interval must be re-evaluated by serial ECGs; if possible, specialist advice may be sought before considering the administration of arsenic trioxide. During arsenic trioxide treatment, potassium concentrations must be maintained above 4 mEq/l and magnesium concentrations above 1.8 mg/dl. Patients whose absolute QT interval value exceeds 500 ms must be re-assessed and immediate action must be taken to correct concurrent risk factors, if present, while the risks and benefits of continuing or discontinuing arsenic trioxide treatment should be considered. If syncope, rapid or irregular heartbeat occurs, the patient should be hospitalised and continuously monitored, serum electrolytes must be evaluated and arsenic trioxide treatment must be temporarily interrupted until the QTc interval decreases below 460 ms, electrolyte abnormalities are corrected and syncope and irregular heartbeat have resolved. After recovery, treatment should be restarted at a dose corresponding to 50% of the previous daily dose. If QTc prolongation does not recur within 7 days of resumption of treatment at the reduced dose, arsenic trioxide therapy may be restarted in the second week at a dose of 0.11 mg/kg body weight per day. If no prolongation occurs, the daily dose may be increased back to 100% of the original dose. Data on the effect of arsenic trioxide on the QTc interval during infusion are not available. Electrocardiograms must be performed twice weekly during induction and consolidation; more frequently in clinically unstable patients. Hepatotoxicity (Grade 3 or higher) In the group of newly diagnosed APL patients at low to intermediate risk, 63.2% of them developed Grade 3 or 4 hepatotoxic effects during induction or consolidation treatment with arsenic trioxide in combination with ATRA (see section 4.8). However, the toxic effects resolved with temporary interruption of arsenic trioxide, ATRA or both. Arsenic trioxide treatment must be discontinued before the planned end of treatment whenever Grade 3 or higher hepatotoxicity is detected based on the National Cancer Institute Common Toxicity Criteria. Once bilirubin, SGOT and/or alkaline phosphatase concentrations decrease below four times the upper limit of normal, arsenic trioxide treatment should be restarted at a dose corresponding to 50% of the previous dose during the first 7 days. Thereafter, if the previous toxicity does not recur, arsenic trioxide treatment may be resumed at full dose. If hepatotoxicity recurs, arsenic trioxide treatment must be permanently discontinued. Dose adjustment Arsenic trioxide treatment must be temporarily interrupted before the end of the treatment cycle whenever Grade 3 or higher toxicity is observed according to the National Cancer Institute Common Toxicity Criteria and this toxicity is considered to be possibly related to arsenic trioxide treatment (see section 4.2). Laboratory tests Serum electrolyte and blood glucose levels, haematological and renal parameters, coagulation parameters and liver function tests must be monitored at least twice weekly during the induction phase, more frequently in clinically unstable patients, and at least once weekly during the consolidation phase. Renal impairment Since no data are available for all groups of renal impairment, caution is recommended when using arsenic trioxide in patients with renal impairment. Experience in patients with severe renal impairment is insufficient to determine whether dose adjustment is necessary. The use of arsenic trioxide in patients undergoing dialysis has not been studied. Hepatic impairment Since no data are available for all groups of hepatic impairment and hepatotoxic effects may occur during treatment with arsenic trioxide, caution should be exercised when using arsenic trioxide in patients with hepatic impairment (see section 4.4 on hepatotoxicity and section 4.8). Experience in patients with severe hepatic impairment is insufficient to determine whether dose adjustment is necessary. Elderly population Only limited clinical data are available on the use of arsenic trioxide in the elderly. Caution should be exercised in these patients. Hyperleukocytosis Treatment with arsenic trioxide in some patients with relapsed/refractory APL was associated with the development of hyperleukocytosis (≥ 10 x 103/μl). There appeared to be no correlation between baseline white blood cell count and the development of hyperleukocytosis, nor a correlation between the baseline white blood cell count and the peak white blood cell count. Hyperleukocytosis was never treated with additional chemotherapy and resolved with continued arsenic trioxide treatment. White blood cell counts during consolidation were not as high as during induction treatment and remained up to 10 x 103/μl, with the exception of one patient whose white blood cell count during consolidation was 22 x 103/μl. Twenty patients with relapsed/refractory APL (50%) developed leukocytosis; however, white blood cell counts in all these patients were decreasing or had normalised by the time bone marrow remission occurred, and cytotoxic chemotherapy or leukapheresis was not required. In 35 of 74 (47%) newly diagnosed APL patients at low to intermediate risk, leukocytosis developed during induction therapy (see section 4.8). However, all cases were successfully treated with hydroxycarbamide. In patients with newly diagnosed or relapsed/refractory APL who develop chronic leukocytosis after initiation of treatment, hydroxycarbamide should be administered. Hydroxycarbamide at the appropriate dose should be continued to maintain a white blood cell count of ≤ 10 x 103/μl, and the dose should then be gradually tapered. Table 1 Recommendations for initiating hydroxycarbamide treatment White blood cell count Hydroxycarbamide 10-50 x 103/µl 500 mg four times daily > 50 x 103/µl 1,000 mg four times daily Development of secondary primary malignancies The active substance of Arsenic trioxide Accord, arsenic trioxide, is a human carcinogen. Monitor patients for the development of secondary primary malignancies. Encephalopathy Cases of encephalopathy have been reported during treatment with arsenic trioxide. Wernicke's encephalopathy has been reported following arsenic trioxide treatment in patients with vitamin B1 deficiency. After initiation of arsenic trioxide, patients at risk of vitamin B1 deficiency should be carefully monitored for signs and symptoms of encephalopathy. Some cases resolved following vitamin B1 administration. Excipient with known effect This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say it is essentially 'sodium-free'.

ARSENIC TRIOXIDE ACCORD 1MG/ML Concentrate for solution for infusion

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